Phenomena characterized by the increase of eosinophils in blood or tissues, namely, their differentiation, induction and infiltration, are recognized in many diseases. For clinical purposes, it is important to distinguish between two groups of diseases, those in which the increase of eosinophils is often observed but is not assumed to participate directly in their pathophysiology and those in which eosinophils are believed to participate in their pathophysiology as the primary immunocytes. Diseases of the first group include Addison's disease, ulcerative colitis and the like. Diseases of the second group include verminations, hypereosinophilic syndrome (HES), eosinophilic pneumonia, eosinophilic enterogastritis and the like, as well as bronchial asthma. Eosinophils are closely involved in the pathophysiology of bronchial asthma and the pathophysiological concept, "eosinophilic bronchitis" is becoming established in these days. In particular, the actions of eosinophils participating in the diseases under consideration share several features, that may be summarized as the following three points: 1) accelerated eosinophil production and differentiation by interleukin-5 (IL-5) and other eosinophil growth lymphokines; 2) migration and accumulation of eosinophils in involved organs due to the eosinophil chemotactic activity; and 3) the activation of eosinophils in foci and the extension of their life survival. In the diseases under consideration, these three factors and events are believed to cause eosinophils to exhibit their cytotoxic and inflammation inducing actions, thereby participating in the pathophysiology of the diseases although their lesions, the severity of their clinical symptoms and other factors may vary to some extent Shigenori Nakajima and Jun'ichi Chihara, Kosankyu no Rinshoshindanjo no Igi (Significance of Eosinophils in Clinical Diagnosis), in "Kosankyo (Eosinophils)", Sohei Makino and Takashi Ishikawa (eds.), pp. 165 -173, Kokusai Igaku Shuppan, 1991!.
Therefore, compounds that can inhibit the increase or activation of eosinophils in blood or tissues have the potential of application to diseases in which eosinophils are believed to participate as primary immunocytes in their pathophysiology, namely, virminations, hypereosinophilic syndrome (HES), eosinophilic pneumonia, eosinophilic enterogastritis, bronchial asthma, etc.
The sole therapeutic approach currently taken against diseases that manifest the increase of eosinophils is symptomatic treatments involving the administration of steroids and no treatment methods are available that target against eosinophils. Steroids cause frequent occurrence of characteristic side effects such as the lowering of resistance to bacterial infections, hyperglycemia, glycosuria, gastric ulcer, hypercalcemia, osteoporosis and obesity. In addition, the method of using steroids is strictly regulated as exemplified by prohibition of sudden discontinuation of administration and, hence, the use of steroids is extremely difficult from a practical viewpoint. Conventional drugs for curing asthma have primarily been based on their ability to inhibit histamine release, however, it has become increasingly clear that eosinophils are also involved closely in the pathophysiology of asthma and targeting against eosinophils is believed to have the potential of application to asthma which cannot be completely cured by existing methods. Under these circumstances, compounds that are safe and which yet have great potency in controlling eosinophils will provide a radical therapy for various diseases in which the increase of eosinophils is involved and, hence, the development of such compounds useful for pharmaceutical composition is sincerely awaited.
Nitorogen-containing tricyclic compounds such as imidazoquinoline derivatives are already known and U.S. Pat. No. 3,200,123 teaches 2-substituted-5,6-dihydroimidazoij!quinoline derivatives having an anti-inflammatory action; however, due to the total absence of disclosed pharmacological data, details about the potency of the individual compounds and the mechanism of their action are unknown. The inventors of the patent reported in Journal of Organic Chemistry, Vol. 25, pp. 1138-1147, 1960 that only part of the dihydroimidazoij!quinoline derivative compounds mentioned above were effective in an animal edema model prepared with dextran sulfate. However, neither prior art reference describes the action on eosinophils. According to Journal of Medicinal Chemistry, Vol. 28, pp. 298-302, 1985, 6-oxo-6H-imidazo4,5,1-ij!quinoline-4-carboxylic acid derivative inhibited a rat passive cutaneous anaphylaxis (PCA) reaction. However, this compound not only differs in structure from the compounds of the present invention, but the prior art also fails to teach the inhibitory effect of the compound on the increase or activation of eosinophils; what is more, this prior art compound was reported to have significant renal toxicity and cause a serious side effect by inhibiting the gain in the body weight of rats.
Another teaching of imidazoquinoline derivatives is found in Unexamined Published Japanese Patent Application Hei 3-27382, which shows the diuretic action of dihydroimidazoquinoline oxime sulfonic acid derivatives. According to WO93/22313, imidazoquinoline and pyrroloquinoline derivatives, both being nitrogen-containing tricyclic compounds, inhibited IgE production in mice. However, the imidazoquinoline derivatives taught in these prior art references have different structures from the compounds of the present invention and there is no teaching at all of their action on eosinophils.
The situation is the same with other compounds having a nitrogen-containing tricyclic skeleton and no reports have ever been made on their action against eosinophils.
It is generally important in the development of pharmaceuticals that they exhibit satisfactory results not only in pharmacological tests but also in safety tests such as a subacute toxicity test (e.g. two-week drug tolerance test in rats), chronic toxicity test, reproduction and genesis toxicity test, mutagenicity test, carcinogenicity test and metabolism test. It is very useful to provide drugs that are highly safe (i.e., exhibiting satisfactory endogenous kinetics as evidenced by the absence of any disorders in drug metabolism mediated by hepatic cytochrome P450 or any serological or pathological disorders), that prove effective in smaller doses and that are easy to handle; however, no compound inhibiting eosinophils that can meet these requirements have been taught in the prior art.